Abstract 1865: Development of CTIM-76, a highly specific Claudin 6 bispecific antibody for treatment of ovarian cancer
Authors: Joseph Rucker, Ileine Sanchez, Kyle Doolan, Breanna Tyrell, Anna Lobley, Nicholas Molino, Kristen Shema, Kyle Guldner, Hayley Roth, Alyssa Cunningham, Kate Slovik, Riley Payne, Eric Butz, Evan Dick, Edward Calamai, Ross Chambers
Journal: Cancer Research (2023)

Abstract Solid tumors lead to 580,000 deaths annually in the US, and safe and effective therapeutics for many late-stage solid tumors are lacking. Ovarian cancer alone kills 14,000 people each year, and many patients do not respond to currently available treatments. Here we introduce CTIM-76, a CLDN6 T-cell engager antibody as a potential treatment of ovarian, endometrial, and other solid tumors. The tight junction protein Claudin 6 (CLDN6) is a validated therapeutic target for many solid tumor types, including ovarian, endometrial, testicular, and gastric. It is differentially expressed on cancer cells with no reported expression in normal, healthy tissue. Despite being an attractive target, therapeutic monoclonal antibodies (MAbs) targeting CLDN6 are difficult to discover due to an abundance of closely related family members and an absolute need for high specificity. The extracellular region of CLDN6 closely resembles the widely expressed family member CLDN9 (3 amino acids different). The few CLDN6 MAbs in clinical development have demonstrated significant binding to other CLDN family members and most have now been halted from further development. Starting with a panel of highly specific CLDN6 antibodies, we engineered a large set (&amp;gt; 50) of CLDN6xCD3 bispecific antibodies (CLDN6 bispecifics) using multiple formats and CD3 arms that encompass different geometries and binding stoichiometries, as these factors are expected to play a critical role in the potency of these molecules both in vitro and in vivo. In vitro T cell cytotoxicity and cytokine release assays as well as developability studies were used to select a small panel of antibodies. These were tested in vivo and demonstrated efficacy in xenograft studies in PBMC-engrafted mice. From this smaller panel, we chose a lead molecule, CTIM-76 for IND-enabling studies. CTIM-76 shows a combination of potent killing of CLDN6-expressing cells, no killing of cells expressing other closely related claudin family members, and excellent productivity and developability. The exquisite specificity of CTIM-76 suggests the potential to address the need for potent therapeutic modalities for ovarian and other cancers without compromising patient safety. Citation Format: Joseph Rucker, Ileine Sanchez, Kyle Doolan, Breanna Tyrell, Anna Lobley, Nicholas Molino, Kristen Shema, Kyle Guldner, Hayley Roth, Alyssa Cunningham, Kate Slovik, Riley Payne, Eric Butz, Evan Dick, Edward Calamai, Ross Chambers. Development of CTIM-76, a highly specific Claudin 6 bispecific antibody for treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1865.